Volatile anesthetic effects on glutamate versus GABA release from isolated rat cortical nerve terminals: 4-aminopyridine-evoked release

J Pharmacol Exp Ther. 2006 Jan;316(1):216-23. doi: 10.1124/jpet.105.090662. Epub 2005 Sep 20.

Abstract

Inhibition of glutamatergic excitatory neurotransmission and potentiation of GABA-mediated inhibitory transmission are possible mechanisms involved in general anesthesia. We compared the effects of three volatile anesthetics (isoflurane, enflurane, or halothane) on 4-aminopyridine (4AP)-evoked release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes). Synaptosomes were prelabeled with l-[(3)H]glutamate and [(14)C]GABA, and release was evoked by superfusion with pulses of 1 mM 4AP in the absence or presence of 1.9 mM free Ca(2+). All three volatile anesthetics inhibited Ca(2+)-dependent glutamate and GABA release; IC(50) values for glutamate were comparable to clinical concentrations (1-1.6x MAC), whereas IC(50) values for GABA release exceeded clinical concentrations (>2.2x MAC). All three volatile anesthetics inhibited both Ca(2+)-independent and Ca(2+)-dependent 4AP-evoked glutamate release equipotently, whereas inhibition of Ca(2+)-dependent 4AP-evoked GABA release was less potent than inhibition of Ca(2+)-independent GABA release. Inhibition of Ca(2+)-independent 4AP-evoked glutamate release was more potent than that of GABA release for isoflurane and enflurane but equipotent for halothane. Tetrodotoxin inhibited both Ca(2+)-independent and Ca(2+)-dependent 4AP-evoked glutamate and GABA release equipotently, consistent with Na(+) channel involvement. In contrast to tetrodotoxin, volatile anesthetics exhibited selective effects on 4AP-evoked glutamate versus GABA release, consistent with distinct mechanisms of action. Preferential inhibition of Ca(2+)-dependent 4AP-evoked glutamate release versus GABA release supports the hypothesis that reduced excitatory neurotransmission relative to inhibitory neurotransmission contributes to volatile anesthetic actions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • 4-Aminopyridine / pharmacology*
  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Dose-Response Relationship, Drug
  • Enflurane / pharmacology
  • Glutamic Acid / metabolism*
  • Halothane / pharmacology
  • In Vitro Techniques
  • Isoflurane / pharmacology
  • Male
  • Nerve Endings / drug effects
  • Nerve Endings / enzymology
  • Nerve Endings / metabolism*
  • Neurotransmitter Agents / metabolism
  • Potassium Channel Blockers / pharmacology*
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / enzymology
  • Presynaptic Terminals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tetrodotoxin / pharmacology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Anesthetics, Inhalation
  • Neurotransmitter Agents
  • Potassium Channel Blockers
  • Glutamic Acid
  • Tetrodotoxin
  • gamma-Aminobutyric Acid
  • Enflurane
  • 4-Aminopyridine
  • Isoflurane
  • Halothane